In the natural environment, organisms are constantly exposed to a wide range of potentially toxic foreign compounds, or xenobiotics. Organisms also produce endogenous toxic compounds that must be metabolized. In mammals, these include bilirubin and bile acids. Because the identities and the concentrations of both exogenous and endogenous toxic agents can change quickly, their management is a complex problem that must be addressed in a flexible and dynamic manner. The nuclear hormone receptors CAR and PXR are central regulators of the response to xenobiotic challenges. In addition, PXR has recently been implicated in bile acid metabolism and preliminary results suggest that CAR is a central regulator of bilirubin clearance. Thus, this proposal is based on the hypothesis that CAR is a key regulator of specific metabolic responses to both exogenous and endogenous compounds. Its long-term goal is to understand these regulatory functions of CAR and their integration with those of PXR and other metabolic regulators. The specific aims are to: 1) use knockout mouse models to identify specific and overlapping target genes for CAR and PXR in liver and other tissues, and determine the consequences of the loss of both the CAR and PXR genes; 2) use knockout mice to define the role of CAR in the response to xenobiotic compounds with important effects on liver metabolism, including the over-the-counter analgesic acetaminophen and the plant-derived hepatoprotectant silybin; and 3) define the role of CAR in the regulation of endogenous metabolic pathways, particularly bilirubin clearance. The xenobiotic response resembles the immune response in interesting ways. For example, both produce specific and appropriate responses to an extremely diverse array of potential threats. Increased understanding of the complex regulation of immune responses has led to significant insights into pathological processes and also to new therapeutic avenues. We believe that a better understanding of the xenobiotic response may generate analogous benefits.